Series of new n-(5-nitro-2-furfurylidene)-3-amino-2-iminooxazolidines



United States Patent SERIES OF NEW N-(S-NITRO-Z-FURFURYLIDENE)3-AMlNO-2-IMINOOXAZOLIDINES No Drawing. Application August 10, 1953,Serial No. 373,438

6 Claims. (Cl. 260-240) This invention relates to a new series ofchemical compounds. The series consists of a number of closely-relatedN-(5-nitro-2-furfurylidene)-3-amino-2-iminooxazolidines and the saltsthereof. They are described by the general formula:

OH-OH wherein n represents an integer from -1,

R is a member of the group consisting of hydrogen and lower alkyl, and

R1 is a member of the group consisting of hydrogen and lower alkyl.

The salts of the compounds which are described by the general formulaabove can be readily and conveniently prepared by neutralization of thebases with acids such as hydrochloric, sulfuric and (i-naphthalenesulfonic.

The new compounds of the series, while possessing anti-microbialproperties, are particularly useful as intermediates for the preparationof members of a series of N nitro 2 furyl) alkylidene -"3 amino 2-oxazolidones. The latter compounds, which form the subject matter ofpending application Serial No. 274,066, filed February 28, 1952, andowned by the assignee of this application, upon which U. S. Patent No.2,742,462 has issued possess a high order of in vivo chemotherapeuticeffectiveness against microbial infections upon oral administration.

In order that our invention may be entirely available to those skilledin the art, methods for making a number of the new compounds of theseries are described briefly and, in conjunction therewith, the utilityof our new compounds in the preparation of a chemotherapeutically activeN-(S-nitro-Z-furyl) alkylidene-3-amino-2 oxazolidone is pointed out:

EXAMPLE I N 5 -nitr0-2-furfurylidene) -3-ar nino-2-iminooxazolidine 0Hzon In a 22 liter, three-necked flask provided with a reflux condenser,stirrer and thermometer are placed 2.32 kg. of 5-nitro-2-fura1dehyde2-(2-hydroxyethyl)-semicarbazone and 7 liters of dry benzene. To thewell stirred suspension is added a solution of 4.9 kg. of thionylchloride in 5 liters of benzene, with heating and at such a rate as tomain tain the temperature at 40-45 C. After the heavy gas evolution hasabated, the suspension is heated at 55-65 C.

ice

for one houhfThe mixture is cooled and the solid filtered with suction.The yield of N-(S-nitro-Z-furfurylidene)-3- amino-2 iminooxazolidinehydrochloride is 2.40 kg. (96%). M. P. 190' C. This is converted to thefree base by dissolving it'in a minimum of water, clarifying andprecipitating with a cold solution of 10% sodium carbonate. This can befurther purified by recrystallization from ethyl alcohol, M. P. 170-17lC,

The. free base. N-(5-nitro-2-furfurylidene) -3-amino-2-iminooxazolidine, dissolved in the minimum quantity of boiling methanolis treated with a slight excess of concentrated sulfuric acid. Oncooling, the acid sulfate crystallizes, melting point 203 C. withdecomposition. Similarly, treatment of the same free base in hotmethanol with excess B-naphthalene sulfonic acid yields the neutral saltof melting point ZZZ-224 C. with decomposition.

The N-(5-nitro-2-furfurylidene)-3 amino 2 iminooxazolidine hydrochloridecan be converted to the corresponding 2-oxazolidone by the action ofcold nitrous acid or by heating with water or dilute acid. An example ofthe use of nitrous acid follows:

Technical N-(S-nitro 2 furfurylidene) 3 amino-2- iminooxazolidinehydrochloride (900 g.) is dissolved in 10 liters of warm water andfiltered to remove a small amount of insoluble material. The solution iscooled to 5-7 C. in an ice bath and by addition of 5 kg. of chopped ice.Glacial acetic acid (1500 cc.) is then introduced. Sodium nitrite (3.40kg.) is added with cooling and stirring during thirty minutes. Somefoaming results and a yellow precipitate forms very rapidly. After fourhours the solid is filtered with suction and dried to constant weight atC. This crude product is purified by recrystallization from glacialacetic acid. The yield of N-(S-nitro-Z-furfurylidene)-3-amino-2-oxazolidone is 442 g., (60%) of M. P. 253-256C.

EXAMPLE II N -,8- (5 -ni tr0-2-furyl acrylal-3 -amin0-2-iminooxazolidineForty-one and six-tenths grams of ,B-(S-nitro-Z-furyl) acrolein2-(2-hydroxyethyl)semicarbazone of M. P. 209- 210 C. (prepared from5-nitro-2-furylacrolein and 2- hydroxyethylsemicarbarbazide) is treatedrapidly with 250 cc. of thionyl chloride in a large beaker. Gas isevolved and the red solid rapidly becomes yellow. After standing at roomtemperature for twelve hours the yellow solid is filtered and washedrepeatedly with dry ether, yield 44.7 g. ofN-(5-nitro-2-furyl)acrylal-3-amino-2-iminooxazolidine hydrochloride ofM. P. 229 C. with decomposition. This hydrochloride is converted to thefree base by dissolving it in cold water, clarifying, follwed bytreatment with sodium carbonate solution to'pH of about 9. The orange,voluminous precipitate of the free base is filtered, washed with water,well dried and recrystallized from absolute ethanol. It melts at 182 C.with resolidification on further heating. Yeld 32.3 g.

The crude N-(5-nitro 2-furyl)acrylal-3-amino-3-iminooxazolidine can beconverted to the corresponding oxazolidone by heating with dilute acid.

Twenty-eight grams of N- (5-nitro-2-furyl)acrylal-3-amino-Z-i-minooxazolidine is dissolved in 1250 cc. of water containing13 cc. of concentrated hydrochloric acid. The clarified solution isboiled for thirty minutes and the precipitated solid filtered from thehot solution. Thefiltrates are reboiled and refiltered after thirtyminutes and the process repeated until no further solid forms. Thecrude. product thus collected (23.2 g.) is a mixture of" the 5-nitro-2furylacrolein derivatives of 3-amino-2- oxazolidone and" of-2-(2-hydroxyethyl)semicarbazide. These are separated by treatment withthionyl chloride in benzene which converts thehydroxyethyl.semicarbazide derivative. to the. water soluble3eamino-2=iminooxazolidine hydrochloride compound, which can berecycled. Four cycles of this process yield 20.2 g. of'N-(S-nitro-2-furyl)'acrylal 3 amino-2-oxazolidone. This can be purified bycrystallization from nitromethane to give a yellow material'of MLP. 270C. dec.

EXAMPLE III N- (S-niZrO-Z-furfuryIidene)'-3-amin0-5 methyl-2-iminooxazolidihe emotion.

A. solution of. 2.-(2-hydroxypropyl)semicarbazide is prepared by thetreatment of l-hydrazino-Z-propanol with potassium cyanate. To thissolution is. added S-nitro- 2-furaldehyde to give5-nitro-2pfuraldehydc-2-(2%hydroxypropyl)semicarbazoneM. P. l95-196'C.

Twenty grams. of 5-nitro-2-furaldehyde 2-(2,-hydroxypropyl)semicarbazone are added to 63.6 cc. of thionyl chloridewhile cooling in an ice bath. The temperature rises to 40 C. and gas-isevolved. When the. violent reaction has subsided. the mixtureis-allowedito stand at room temperature for forty-five minutes- The darkbrown. solution is then poured. into 5002 cc. of ether, which causesprecipitation of gummy crystals of crude N-(S-ni-tro-Z-furfurylidene)-3-amino-5-methyl-2riminooxazolidine hydrochloride. This is converted tothe free base by dissolving; it in a ofv cold water, adding. sodiumcarbonate: solution until mildly alkaline, and. re-

moving by filtration the resulting precipitate. The dried.

precipitate is recrystallized from nitromethane, M. P. 170-173 C.

The crude N-(S-nitro-Z-furfurylidene-)-3-amino-5-methyl-Z-iminooxazolidine hydrochloride is suitable for conversion tothe oxazolidone. The yellow crystals are dissolved in, 150.. cc.ofwater, filteredtfree of any insoluble matter, 8.5 cc. of concentratedsulfuric acid is added and the solution refluxed for fifty minutes. Ayellow solid gradually separates, which is filtered from the hotsolution, washed. with. warm water. and. dried to constant weight at 100to give. 8.1 grams of N-(5'-nitro-2.-furfurylidene.) -3amino-5methyl-Z-oxazolidone. ofi M. P- 248-252 0., yield 43%.

Recrystallization from glacial acetic acid; raises:- the M. P; to252-254 0.

EXAMPLE IV' N 5 -nitr-2-furfurylidene) -3 -amina- -n.-butyl-2-iminooxazolidine, hydrochloride.

. I 4.. Z-iminooxazolidine hydrochloride in water converts it to N-(-5-nitro- 2-- furfurylidene) -3-amino 5'- n-butyl-Z- oxazolidone, M. P.194 C.

EXAMPLE V N (5 nitro 2 furfurylidene) 3 amino 4 methyl-Z-iminooxazolidine hydrochloride A solution of 2-(l -methyl 2hydroxyethyl)semicarbazide is prepared by the. treatment of2,-hydrazino-1-propanol with potassium cyanate. To this solution isadded 5-nitro-2-furaldehyde to give 5-nitro-2-furaldehyde 2-(1-methyl-Z-hydroxyethyl)semicarbazone, M. P. 204-205 C.

To- 0.6 g. of 5-nitro-2-furaldehyde2-(1-methyl-2-hydroxyethyl)semicarbazoneis-added 5' cc. of thionylchloride. Gas evolution takes place and the color-of the solid changesto very light yellow. The N-(5-nitro-2-furfurylidene) 3 amino 4 methyl 2iminooxazolidine hydrochloride thus obtained weighs 0.60 g., 94%, M. P.202203 C. When-.asolution of 0.5 g. of this compound in l0-cc. of wateris refluxed for one hour, a yellow solid is precipitated. This solid,N-(5-nitro-2-furfurylidene)-3-amino-4-methyl-2-oxazolidone, M. P.199-200 C., weighs 0.25 g., 58%.

What is claimed is:

1. A member of the group, consisting of, a compound represented; by theformula:

wherein;

n. represents an integer from. 0-1

Rv is atmember-of the group consisting of hydrogen and lower alkyl, and.

Kris amemberof the groupconsisting of hydrogen and lower alkyl',

and acid. addition salts thereof.

2. N (5 nitro 2 furfurylidene) 3 amino 2- iminooxazolidine representedby the formula:

3. N ,8 (5 nitro 2.- furyDacrylal 3 amino 2- iminoozazolidinerepresented by the formula:

4 N 5, nitro 2 furf urylidene). 3 amino 5- methyl-Z-iminooxazolidinerepresented by the formula:

7 5. N (5 niti'o 2 furfurylidene) 3 amino 5 nmethyl-2-iminooxazolidinehydrochloride represented by butyl-Z-iminooxazolidine hydrochloriderepresentcd by the formula:

the formula:

I 5 om-n n-cH=NN -o=NE v H 1 CH=NN...O=NH 0 c 0 CH:- H-C: CH|CCHKCHQ1CHI6. N (5 nitro 2 furfurylidene) 3 amino 4- 10 No references cited.

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND REPRESENTED BY THEFORMULA: